: A clearer understanding of Alzheimer's disease (AD) pathogenesis, and cognitive decline in general, may provide opportunities for therapeutic interventions to slow the progression of cognitive decline and improve the quality of life in elderly populations. The long-term goal of this proposal, ?Microbiota-Brain Axis in Alzheimer's Disease: MIND Diet-Induced Effects? is to identify the intestinal profile (i.e., dysbiosis, barrier dysfunction) as a critical regulator of cognitive decline. Our objective is to identify an abnormal or sub-optimal intestinal profile that promotes or exacerbates cognitive decline, identify immune mechanisms, and find therapeutic targets that can slow the progression of cognitive decline. Our central hypothesis is that an unfavorable intestinal profile is a risk factor for cognitive decline. To test our hypothesis we will leverage an exciting phase III trial recently funded by the National Institute on Aging evaluating the ability of a dietary intervention to slow the progression of AD pathogenesis (?MIND Diet Intervention to Prevent Alzheimer Disease,? AG052583). The trial will recruit subjects aged 65-84 who are cognitively normal but with a family history of AD and randomly assign them to a dietary intervention or the usual diet to determine the impact of a diet on cognitive decline over three years. The rationale for the proposed research is that the intestinal microbiota affects brain function and behavior and this occurs via several mechanisms including microbiota-derived metabolites (short chain fatty acids (SCFA)) and the immune system (dendritic cells (DC), TH1, TH2, T regulatory cells (Tregs)). Many lifestyle choices and diseases influence the intestinal microbiota, but none more robustly than diet. Diets such as the Mediterranean and Dietary Approaches to Stop Hypertension (DASH) improve cardiovascular health and delay cognitive decline and we propose that they do so by inducing a more favorable intestinal profile including: (1) decreased pro-inflammatory bacteria (e.g., Firmicutes/Bacteroides ratio), (2) increased beneficial SCFA- producing bacteria (e.g., Blautia, Roseburia), (3) increased stool and serum SCFA content, (3) improved intestinal barrier integrity (e.g., reduced serum lipopolysaccharide), (4) altered immune system (dendritic cells, T cells, monocytes), and (5) reduced systemic inflammation. We will identify an intestinal profile that predicts cognitive decline, determine how a dietary intervention that delays cognitive decline impacts the intestinal profile, identify an intestinal profile that most benefits from the dietary intervention, and evaluate potential mechanisms including bacterial-derived metabolites and the immune system. Successful completion of this study is expected to identify the intestinal profile as a factor that contributes to cognitive decline and begin to identify mechanisms by which a dietary intervention may delay cognitive impairment. These studies will have a positive impact by highlighting the importance of the microbiota-brain axis, and should be of value for understanding AD pathogenesis and identifying potential therapeutic targets.